scholarly journals SAT-LB15 24-Month Efficacy and Safety of Once Weekly and Every Other Week Administration of GX-H9, Hybrid FC-Fused Long-Acting Human Growth Hormone: A Phase 2 Study in Children With Growth Hormone Deficiency

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Oleg Malievskiy ◽  
Aryaev Mykola ◽  
Nataliya Zelinska ◽  
Elena Bolshova ◽  
Ganna Senatorova ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Treatment Period ◽  
Study Drug ◽  
Hormone Deficiency ◽  
Height Velocity ◽  
First Year ◽  
Efficacy And Safety ◽  
Second Year ◽  
Long Acting

Abstract Objectives GX-H9 is a long-acting form of recombinant human GH under clinical development for both adults and children with GHD. In this report, 24-month efficacy and safety of once weekly and every other week (EOW) administration of GX-H9 were evaluated, in addition to Genotropin® switch-ability to GX-H9 after 12-month of treatment. Methods Subjects were randomly assigned to receive either one of three doses of GX-H9 (0.8 mg/kg/week, 1.2 mg/kg/week or 2.4 mg/kg every other week) or 0.03 mg/kg/day of Genotropin®. Treatment duration is 24-month for all patients in GX-H9 arms while patients in Genotropin® arm were re-randomized to one of three doses of GX-H9 at the completion of the first 12-month of treatment. Doses of GX-H9 were adjusted throughout the treatment period whenever necessary, based on IGF-1 levels. Results Out of 56 randomized, 54 received either GX-H9 or Genotropin®. Fifty subjects completed the 12-month treatment period. Of 50, 45 subjects completed the next 12-month, comprising 33 patients from GX-H9 and 12 patients who switched from Genotropin®. First year/second year mean±SD annualized height velocity (aHV) for 0.8 mg/kg/week, 1.2 mg/kg/week or 2.4 mg/kg every other week of GX-H9 were 10.50±2.54/9.14±1.96, 11.76±1.96/9.88±1.92 and 11.03±2.92/9.72±1.90 cm/year, respectively. First year mean±SD aHV for Genotropin® was 9.14±3.09 cm/year. Patients switched to one of the three doses of GX-H9 in the second year showed comparable aHV in the second year (8.73±2.69/7.60±0.90/9.13±1.07 cm/year for 0.8 mg/kg/week, 1.2 mg/kg/week and 2.4 mg/kg/EOW GX-H9, respectively). No significant slow-down of the growth was observed in the second year from patients who received GX-H9 throughout and patients who switched from Genotropin®. Mean change in height SDS after 12 months/24 months of GX-H9 treatment throughout from baseline treatment improved continuously (+1.10/+1.61 and +1.31/+1.89 and +1.15/+1.69 for 0.8 mg/kg/week, 1.2 mg/kg/week and 2.4 mg/kg EOW GX-H9, respectively). First year mean change in height SDS for Genotropin® was +0.92 SDS, and showed comparable improvement in height SDS after switching to GX-H9 weekly arms (+0.76 and +0.79 SDS for 0.8 mg/kg/week and 1.2 mg/kg/week, respectively). Most treatment-emergent adverse events were evaluated as unrelated to the study drug and were mild or moderate in severity. No new safety concerns were observed throughout 24 months of long-term GX-H9 treatment or after switching to GX-H9 from Genotropin®.Conclusions Growth response and safety profile of GX-H9 in children with GHD is comparable to those of daily GH, achieving robust growth rates after 24-month treatment. Subjects switched from Genotropin® in the second year, also showed substantial catch-up growth indicated by improvement in height SDS. GX-H9 has a unique potential to be a convenient long-term GH providing not only weekly but also twice-monthly treatment.

scholarly journals Once-Weekly Somapacitan Versus Daily Growth Hormone in Growth Hormone Deficiency: 2-Year Efficacy Results From REAL 3, a Randomized Phase 2 Trial

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A680-A680
Author(s):  
Lars S Sävendahl ◽  
Tadej Battelino ◽  
Michael Højby Rasmussen ◽  
Reiko Horikawa ◽  
Paul Saenger
Keyword(s):  
Growth Hormone ◽  
Standard Deviation ◽  
Height Velocity ◽  
First Year ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Gh Treatment ◽  
Treatment Groups ◽  
Igf I ◽  
Second Year

Abstract Current treatment for growth hormone (GH) deficiency (GHD) requires daily injections, which can be burdensome for the patients/caregivers. Once-weekly somapacitan is a long-acting GH derivative currently in phase 3 for use in children with GHD and phase 2 for short children born small for gestational age. A phase 2, multinational, randomized, open-label, controlled trial (NCT02616562) investigated the efficacy and safety of somapacitan in children compared with daily GH (Norditropin®). GH-treatment-naïve prepubertal children with GHD received 0.04 (n=16), 0.08 (n=15) or 0.16 mg/kg/week (n=14) subcutaneous (s.c.) somapacitan, or s.c. daily GH 0.034 mg/kg/day (0.24 mg/kg/week; n=14) for 52 weeks, followed by a 104-week safety extension. In the extension phase, all patients on somapacitan received 0.16 mg/kg/week; daily GH dose remained unaltered. The 52-week efficacy and safety results have been reported previously. We report here the efficacy results after 104 weeks of GH treatment. At week 104, mean (standard deviation [SD]) height velocity (HV) in the first year of the safety extension was: 10.6 (1.4), 10.0 (1.6) and 9.2 (1.7) cm/year for 0.04/0.16 mg/kg/week (n=13), 0.08/0.16 mg/kg/week (n=15) and 0.16/0.16 mg/kg/week (n=14) somapacitan, respectively, versus 9.0 (2.3) cm/year for daily GH (n=11). Mean (SD) change from baseline in HV standard deviation score (SDS) was 8.04 (2.52), 6.21 (2.90) and 6.40 (3.04) for somapacitan, respectively, versus 6.58 (3.15) for daily GH. Compared with week 52, mean HV and HV SDS at week 104 were increased in children in the somapacitan 0.04/0.16 mg/kg/week and 0.08/0.16 mg/kg/week treatment groups. Height SDS values improved during the second year of treatment with somapacitan and daily GH, with the greatest change from baseline in the somapacitan 0.16/0.16 mg/kg/week treatment group. The mean (SD) change in height SDS from baseline to week 104 was 1.73 (0.76), 1.87 (0.81) and 2.18 (1.18) for somapacitan, respectively, versus 1.72 (0.65) for daily GH. The observed mean (SD) change in insulin-like growth factor-I (IGF-I) SDS from baseline was similar between the somapacitan 0.08/0.16 and 0.16/0.16 mg/kg/week treatment groups (3.15 [1.17] and 3.21 [1.12], respectively), and slightly higher compared with IGF-I SDS in the 0.04/0.16 mg/kg/week group (2.99 [1.05]) and the daily GH group (3.06 [1.26]). Mean IGF-I SDS values remained below the upper limit (+2) of the normal range for all treatment groups throughout the 104-week trial duration. Somapacitan was well tolerated at all doses investigated, with no new safety or local tolerability issues identified during the 104 weeks of treatment. In conclusion, at week 104, height-based outcomes were similar between somapacitan 0.16/0.16 mg/kg/week and daily GH, with comparable mean change in IGF-I SDS. Furthermore, the key improvements observed in the first year were maintained in the second year of the study.

scholarly journals Reduced Effectiveness and Comparable Safety in Biweekly vs. Weekly PEGylated Recombinant Human Growth Hormone for Children With Growth Hormone Deficiency: A Phase IV Non-Inferiority Threshold Targeted Trial

2021 ◽  
Vol 12 ◽  
Author(s):  
Chengjun Sun ◽  
Biao Lu ◽  
Yu Liu ◽  
Yaqin Zhang ◽  
Haiyan Wei ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Deficiency ◽  
Human Growth Hormone ◽  
Recombinant Human Growth Hormone ◽  
Human Growth ◽  
Hormone Deficiency ◽  
Height Velocity ◽  
Clinical Trial Registration ◽  
Long Acting ◽  
Phase Iv

ContextLong-acting recombinant human growth hormone (rhGH) has transformed growth hormone deficiency (GHD) treatment. However, the possibility and rationality for flexible time regimen are pending.ObjectiveWe studied the efficacy of biweekly versus weekly PEGylated rhGH (PEG-rhGH) therapy in GHD children.Design, Setting, and PatientsThis multicenter, phase IV trial with a non-inferiority threshold ≥20% enrolled 585 Tanner stage I GHD children.InterventionSubjects randomly received 0.20 mg/kg once-weekly or biweekly PEG-rhGH, or 0.25 mg/kg.w rhGH once daily for 26 weeks.Main Outcome MeasureThe primary outcome was height SD scores for chronological age (HtSDSCA) at week 26 and safety measurements including adverse events (AEs), IGF-2, and IGFBP-2 changes.ResultsAt week 26, the median HtSDSCA changed from −2.75, −2.82, and −2.78 to −2.31, −2.43, and −2.28 with weekly and biweekly PEG-rhGH, and daily rhGH, respectively. The difference in HtSDSCA was 0.17 ± 0.28 between weekly and biweekly PEG-rhGH, and 0.17 ± 0.27 between daily rhGH and biweekly PEG-rhGH, failing the non-inferiority threshold. Nevertheless, the height velocity of children receiving biweekly PEG-rhGH reached 76.42%–90.34% and 76.08%–90.60% that of children receiving weekly PEG-rhGH and daily rhGH, respectively. The rate of AEs was comparable among the groups. No statistical difference was observed in IGF-2 and IGFBP-2 levels among the groups. IGFBP-2 levels decreased over time in all groups, with no notable difference in IGF-2 and IGFBP-2 changes among the three treatment groups.ConclusionsAlthough notably promoted height velocity, biweekly PEG-rhGH failed the non-inferiority threshold as compared with either weekly PEG-rhGH or daily rhGH. Compared with short-term rhGH, long-acting PEG-rhGH did not significantly increase tumor-associated IGF-2 and IGFBP-2 expressions.Clinical Trial Registrationclinicaltrials.gov, identifier NCT02976675.

scholarly journals OR10-05 Phase 3 FliGHt Trial: Experience of Switching from Daily Growth Hormone Therapy to Once-Weekly TransCon HGH in Children with Growth Hormone Deficiency

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Aristides K Maniatis ◽  
Ulhas Nadgir ◽  
Paul Saenger ◽  
Gail Mick ◽  
Kent L Reifschneider ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Adverse Event ◽  
Growth Hormone Deficiency ◽  
Study Drug ◽  
Hormone Deficiency ◽  
Height Velocity ◽  
Adverse Event Profile ◽  
Phase 3 ◽  
Daily Growth ◽  
Treatment Naïve

Abstract Background: The Phase 3 fliGHt Trial evaluated children with growth hormone deficiency (GHD) of a broad range of baseline demographics and treatment durations who switched from daily growth hormone (hGH; somatropin) therapy to once-weekly TransCon hGH. TransCon hGH is an investigational long-acting prodrug consisting of 3 components: hGH, an inert carrier that protects it, and a linker that temporarily binds the two. When injected into the body, at physiologic pH and temperature, unmodified hGH is gradually released in a predictable manner. Methods: All subjects initiated open-label once-weekly TransCon hGH 0.24 mg hGH/kg/week irrespective of prior daily hGH dose. Subjects 3 to 17 years old must have been treated with daily hGH for 13 to 130 weeks; subjects 6 months to 3 years old may have been treatment-naïve or treated with daily hGH for ≤130 weeks. The primary objective was to assess safety and tolerability over this 26-week trial. Efficacy measures included annualized height velocity (AHV), height standard deviation score (SDS), and insulin-like growth factor 1 (IGF-1) SDS. Results: Of the 146 enrolled subjects, 98.6% completed the trial. Mean age at baseline was 10.6 years (range: 1, 17). The majority (97.9%) were treatment-experienced with a prior daily hGH mean dose of 0.29 mg/kg/week (range: 0.13, 0.49); 3 subjects were treatment-naïve and <3 years old. Just over half the subjects (56.8%) experienced a treatment-emergent adverse event (TEAE), with only 4.1% of subjects experiencing a TEAE considered related to study drug. No TEAE led to discontinuation of study drug. The type and frequency of TEAEs reported were similar to the published adverse event profile of daily hGH therapies. Mean hemoglobin A1c remained 5.2% at baseline and Week 26. No neutralizing antibodies were detected; low-titer anti-hGH binding antibodies were detected in 2.8% of subjects. Growth outcomes were as expected for this treatment-experienced heterogenous population, with a least-squares mean (LSM) AHV of 8.7 cm/year (95% CI: 8.2, 9.2) at Week 26 and LSM height SDS change from baseline to Week 26 of +0.25 (95% CI: 0.21, 0.29). In the age-defined subgroups, mean observed AHV at Week 26 ranged from 8.2 to 16.2 cm/year and mean observed height SDS change from baseline to Week 26 ranged from +0.23 to +0.96. Of note, the linear relationship between average IGF-1 SDS and TransCon hGH doses demonstrated in previous treatment-naïve trials was preserved in this population of treatment-experienced children who had dose titrations. Conclusions: TransCon hGH treatment outcomes, including AHV and height SDS, were as expected across a diversity of ages, disease characteristics, and treatment experiences, reflective of a real-world setting. Dose titrations of TransCon hGH demonstrated a predictable IGF-1 response. Switching to TransCon hGH resulted in a similar adverse event profile to daily hGH therapy.

scholarly journals SAT-LB16 Maintenance of Favorable Treatment Effect of Once-Weekly TransCon hGH for Children With Growth Hormone Deficiency: Interim Analysis From the Enlighten Long-Term Extension Trial

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Aristides K Maniatis ◽  
Samuel J Casella ◽  
Ulhas M Nadgir ◽  
Gail J Mick ◽  
Paul Hofman ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Treatment Effect ◽  
Interim Analysis ◽  
Hormone Deficiency ◽  
First Year ◽  
Treatment Naïve ◽  
Group A ◽  
Group B ◽  
Extension Trial

Abstract Background Once-weekly TransCon hGH is an investigational long-acting prodrug for growth hormone deficiency (GHD) that consists of 3 components: unmodified growth hormone (hGH; somatropin), an inert carrier that protects it, and a linker that temporarily binds the two. In the randomized phase 3 heiGHt Trial evaluating treatment-naïve children with GHD, TransCon hGH demonstrated superior annualized height velocity and ∆ height standard deviation score (SDS) compared to Genotropin and had a similar safety and tolerability profile. Methods Results are reported from an interim analysis of subjects from heiGHt who continued in the ongoing enliGHten long-term extension trial for 26 weeks. In the 52-week heiGHt Trial, treatment-naïve, prepubertal subjects with GHD were randomized 2:1 to receive once-weekly TransCon hGH 0.24 mg hGH/kg/week or an equivalent weekly dose of daily Genotropin. Subjects completing heiGHt could enroll in enliGHten, where all subjects received TransCon hGH. Two groups were analyzed: Group A (TransCon hGH in both heiGHt and enliGHten) and Group B (Genotropin in heiGHt, followed by TransCon hGH in enliGHten). Safety and growth outcomes were evaluated approximately every 13 weeks in heiGHt and enliGHten. IGF-1 was sampled on postdose Day 5 (±1 day) in enliGHten. A by-visit ANCOVA model was used to analyze numeric efficacy endpoints.ResultsAll but one subject who completed heiGHt continued into enliGHten (A: N=103, B: N=55). Baseline characteristics at the start of heiGHt were balanced between groups. The statistically significant treatment difference in ∆ height SDS (Group A vs B) at the end of heiGHt (Week 52, N=159; 1.10 vs 0.96, P=0.0149) was sustained through Week 78 (N=154; 1.39 vs 1.24, P=0.0436), demonstrating persistence of catch-up growth for both groups and maintenance of superior treatment effect for subjects treated with TransCon hGH in the first year of therapy. At Week 78, least-squares mean (SE) IGF-1 SDS on postdose Day 5 (N=153) was 0.52 (0.15) for Group A and 0.59 (0.19) for Group B. Adverse events (AEs) were comparable between groups during heiGHt. During enliGHten, 48.7% (76/156) and 1.9% (3/156) of subjects experienced AEs and serious AEs, respectively; the AE profile was consistent with what was previously observed in heiGHt. A low titer of anti-hGH binding antibodies were detected in 10/156 (6.4%) subjects during treatment with TransCon hGH in heiGHt and enliGHten; no neutralizing antibodies were detected. Lab parameters (HbA1c, cortisol, free thyroxine) were stable and generally remained within the normal range throughout the trials. Mean (SD) BMI SDS was 0.0 (0.8) for Group A and 0.1 (0.9) for Group B at Week 78.Conclusions Children treated with TransCon hGH showed continued improvement of height SDS beyond the first year. Treatment with TransCon hGH through 78 weeks demonstrated an AE and immunogenicity profile comparable to that of a daily hGH therapy.

Growth hormone therapy in achondroplasia

1993 ◽  
Vol 128 (5) ◽  
pp. 394-396 ◽  
Author(s):  
Yoshikazu Nishi ◽  
Michi Kajiyama ◽  
Shinichiro Miyagawa ◽  
Mitsuhiro Fujiwara ◽  
Kazuko Hamamoto
Keyword(s):  
Growth Hormone ◽  
Hormone Therapy ◽  
Growth Hormone Therapy ◽  
Height Velocity ◽  
First Year ◽  
Gh Therapy ◽  
Gh Treatment ◽  
Gh Secretion ◽  
The Status ◽  
Second Year

The status of growth hormone (GH) secretion together with the effect of GH therapy was studied in six children with achondroplasia. One patient had impaired GH secretion, which may, in part, be due to obesity. The pre-GH-treatment height velocity was 3.8±0.7 cm/year, but this increased to 6.0±1.0 cm/year in the first year of treatment and to 4.4±0.6 cm/year in the second year. One patient who underwent GH therapy for 4 years showed good response in height velocity. A considerable variation was observed in response to GH therapy within the treated cases.

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